AndA, an Fe(II)/α-ketoglutarate
(αKG)-dependent enzyme,
is the key enzyme that constructs the unique and congested bridged-ring
system of anditomin (1), by catalyzing consecutive dehydrogenation
and isomerization reactions. Although we previously characterized
AndA to some extent, the means by which the enzyme facilitates this
drastic structural reconstruction have remained elusive. In this study,
we have solved three X-ray crystal structures of AndA, in its apo
form and in the complexes with Fe(II), αKG, and two substrates.
The crystal structures and mutational experiments identified several
key amino acid residues important for the catalysis and provided insight
into how AndA controls the reaction. Furthermore, computational calculations
validated the proposed reaction mechanism for the bridged-ring formation
and also revealed the requirement of a series of conformational changes
during the transformation.